Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

Szeliga, Monika; Rola, Radosław

doi:10.3390/ijms232415712

Cited by 4 publications

(6 citation statements)

References 39 publications

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“…Moreover, Van Loenhout et al showed that adherent GBM cells were more sensitive to auranofin (AF), an inhibitor of antioxidant thioredoxin reductase, than the relevant cells cultured in neurospheres [46]. Similarly, in our previous study, LUB17N cells showed increased resistance to AF compared to their counterparts cultured as an adherent monolayer [47].…”

Section: Discussionsupporting

confidence: 55%

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Szeliga

Rola

2023

Cells

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Compounds that cause oxidative stress have recently gained considerable interest as potential anticancer treatment modalities. Nevertheless, their efficiency may be diminished by the antioxidant systems often upregulated in cancer cells. Peroxiredoxins (PRDXs) are antioxidant enzymes that scavenge peroxides and contribute to redox homeostasis. They play a role in carcinogenesis and are upregulated in several cancer types. Here, we assessed the expression pattern of PRDX1 and PRDX2 in glioblastoma (GBM) and examined the efficacy of their inhibitors in GBM cell lines and patient-derived GBM cells. Both PRDX1 and PRDX2 were upregulated in GBM compared to non-tumor brain tissues and their considerable amounts were observed in GBM cells. Adenanthin, a compound inhibiting PRDX1 activity, slightly decreased GBM cell viability, while conoidin A (CONA), a covalent PRDX2 inhibitor, displayed high toxicity in GBM cells. CONA elevated the intracellular reactive oxygen species (ROS) level. Pre-treatment with an ROS scavenger protected cells from CONA-induced death, indicating that ROS accumulation plays a crucial role in this phenomenon. Menadione or celecoxib, both of which are ROS-inducing agents, potentiated the anticancer activity of CONA. Collectively, our results unveil PRDX1 and PRDX2 as potential targets for GBM therapy, and substantiate the further exploration of their inhibitors.

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Section: Discussionsupporting

confidence: 55%

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Szeliga

Rola

2023

Cells

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“…Auranofin, an FDA-approved oral drug, known for its clinical safety, is able to penetrate the blood-brain barrier at doses ranging from 0.2 to 5 µmol/L [115]. Inhibition of thiol redox enzymes and inflammation pathways commonly involved in tumor growth instigated repurposing auranofin in studies, revealing the promising anticancer effects of auranofin in various cancer types [54,56,62,64,[116][117][118][119][120][121] alone or as drug combination [46][47][48]. The only clinical trial using auranofin in GBM tested the combination of nine repurposed drugs including auranofin and temozolomide in the CUSP9v3 Treatment Protocol (NCT02770378) for a limited cohort of 10 patients with recurrent GBM.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with auranofin at 3 µM for 24 h significantly increased ROS levels in the three isogenic cell lines compared to their respective controls (U87MG p < 0.001, U87EGFRwt, p = 0.024, U87EGFRvIII p < 0.001) (Figure 2A). Of note, ROS increase was more pronounced in U87/EGFRvIII compared to U87/EG-FRwt (p = 0.033), as shown in Figure 2A Next, we used N-acetylcysteine (NAC), a conventional ROS scavenger [47,58], to determine whether ROS mediate the cytotoxic effects of auranofin in U87/EGFR isogenic cell lines. NAC treatment at 1 or 2 mM for 72 h did not significantly affect cellular metabolic activity or vitality (Figure S3A).…”

Section: Auranofin Increased Ros Along With Ros-dependent Cytotoxicit...mentioning

confidence: 96%

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Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression

Martinez-Jaramillo,

Jamali,

Abdalbari

et al. 2024

Cancers

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Glioblastoma (GBM) is the most prevalent and advanced malignant primary brain tumor in adults. GBM frequently harbors epidermal growth factor receptor (EGFR) wild-type (EGFRwt) gene amplification and/or EGFRvIII activating mutation. EGFR-driven GBM relies on the thioredoxin (Trx) and/or glutathione (GSH) antioxidant systems to withstand the excessive production of reactive oxygen species (ROS). The impact of EGFRwt or EGFRvIII overexpression on the response to a Trx/GSH co-targeting strategy is unknown. In this study, we investigated Trx/GSH co-targeting in the context of EGFR overexpression in GBM. Auranofin is a thioredoxin reductase (TrxR) inhibitor, FDA-approved for rheumatoid arthritis. L-buthionine-sulfoximine (L-BSO) inhibits GSH synthesis by targeting the glutamate–cysteine ligase catalytic (GCLC) enzyme subunit. We analyzed the mechanisms of cytotoxicity of auranofin and the interaction between auranofin and L-BSO in U87MG, U87/EGFRwt, and U87/EGFRvIII GBM isogenic GBM cell lines. ROS-dependent effects were assessed using the antioxidant N-acetylsteine. We show that auranofin decreased TrxR1 activity and increased ROS. Auranofin decreased cell vitality and colony formation and increased protein polyubiquitination through ROS-dependent mechanisms, suggesting the role of ROS in auranofin-induced cytotoxicity in the three cell lines. ROS-dependent PARP-1 cleavage was associated with EGFRvIII downregulation in U87/EGFRvIII cells. Remarkably, the auranofin and L-BSO combination induced the significant depletion of intracellular GSH and synergistic cytotoxicity regardless of EGFR overexpression. Nevertheless, molecular mechanisms associated with cytotoxicity were modulated to a different extent among the three cell lines. U87/EGFRvIII exhibited the most prominent ROS increase, P-AKT(Ser-473), and AKT decrease along with drastic EGFRvIII downregulation. U87/EGFRwt and U87/EGFRvIII displayed lower basal intracellular GSH levels and synergistic ROS-dependent DNA damage compared to U87MG cells. Our study provides evidence for ROS-dependent synergistic cytotoxicity of auranofin and L-BSO combination in GBM in vitro. Unraveling the sensitivity of EGFR-overexpressing cells to auranofin alone, and synergistic auranofin and L-BSO combination, supports the rationale to repurpose this promising pro-oxidant treatment strategy in GBM.

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“…Auranofin is a gold-based compound approved by FDA for rheumatoid arthritis in 1985. Growing evidence has suggested that the drug demonstrates therapeutic effects for infectious diseases ( Capparelli et al, 2017 ; Tunes et al, 2020 ; Wallis et al, 2021 ) as well as for cancers ( Steers et al, 2022 ; Szeliga and Rola, 2022 ). Clinical trials using auranofin for cancer therapy are undergoing (NCT03456700, ovarian cancer; NCT01737502, lung cancers).…”

Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells

Ding,

Cui,

et al. 2023

Front. Chem.

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Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment.

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Menadione Potentiates Auranofin-Induced Glioblastoma Cell Death

Cited by 4 publications

References 39 publications

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production

Pro-Oxidant Auranofin and Glutathione-Depleting Combination Unveils Synergistic Lethality in Glioblastoma Cells with Aberrant Epidermal Growth Factor Receptor Expression

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells

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